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Updated: May 6, 2026
Isolation of Soluble and Insoluble PrP Oligomers in the Normal Human Brain
Published on: October 3, 2012
Small protease sensitive oligomers of PrPSc in distinct human prions determine conversion rate of PrP(C)
Chae Kim1, Tracy Haldiman, Krystyna Surewicz
1National Prion Disease Surveillance Center, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
Abstract:
The mammalian prions replicate by converting cellular prion protein (PrP(C)) into pathogenic conformational isoform (PrP(Sc)). Variations in prions, which cause different disease phenotypes, are referred to as strains. The mechanism of high-fidelity replication of prion strains in the absence of nucleic acid remains unsolved. We investigated the impact of different conformational characteristics of PrP(Sc) on conversion of PrP(C) in vitro using PrP(Sc) seeds from the most frequent human prion disease worldwide, the Creutzfeldt-Jakob disease (sCJD). The conversion potency of a broad spectrum of distinct sCJD prions was governed by the level, conformation, and stability of small oligomers of the protease-sensitive (s) PrP(Sc). The smallest most potent prions present in sCJD brains were composed only of∼20 monomers of PrP(Sc). The tight correlation between conversion potency of small oligomers of human sPrP(Sc) observed in vitro and duration of the disease suggests that sPrP(Sc) conformers are an important determinant of prion strain characteristics that control the progression rate of the disease.
Insights
Prion strains, variations in prions causing different disease phenotypes, replicate without nucleic acid. Small prion oligomers, specifically protease-sensitive PrP(Sc), determine conversion potency and disease progression in Creutzfeldt-Jakob disease.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Mammalian prions, pathogenic isoforms of cellular prion protein (PrP(C)), replicate by conformational conversion.
- Prion strains exhibit distinct disease phenotypes, but the mechanism of their high-fidelity replication without nucleic acids remains unclear.
Purpose of the Study:
- To investigate how conformational characteristics of protease-resistant prion protein (PrP(Sc)) influence the conversion of PrP(C) in vitro.
- To determine the role of PrP(Sc) oligomer size, conformation, and stability in prion strain characteristics.
Main Methods:
- In vitro conversion assays using PrP(Sc) seeds from Creutzfeldt-Jakob disease (CJD) patients.
- Characterization of small oligomers of protease-sensitive PrP(Sc) (sPrP(Sc)) to assess their conversion potency.
Main Results:
- The conversion potency of distinct CJD prions was determined by the level, conformation, and stability of small sPrP(Sc) oligomers.
- The most potent prions identified in CJD brains consisted of approximately 20 PrP(Sc) monomers.
- A strong correlation was observed between the in vitro conversion potency of sPrP(Sc) oligomers and the clinical duration of the disease.
Conclusions:
- Small oligomers of sPrP(Sc) are critical determinants of prion strain characteristics.
- The conformation and stability of these sPrP(Sc) conformers influence the rate of prion-mediated disease progression.
